Costimulation through CD28 suppresses T cell receptor-dependent activation of the Ras-like small GTPase Rap1 in human T lymphocytes.
Members of the Ras superfamily of small molecular weight GTPases play diverse and critical roles in mediating cellular responses to extracellular stimuli, including mitogenesis, cytoskeletal maintenance and rearrangement, and integrin activation. In T lymphocytes, biochemical and genetic evidence demonstrate that Ras plays an essential role in coupling T cell receptor ligation to signaling cascades required for T cell proliferation and development. Recent observations that C3G, a guanine nucleotide exchange factor specific for the Ras-related GTPase Rap1, is recruited into tyrosine-phosphorylated protein signaling complexes in activated T cells have suggested that Rap1 may also play a role in T cell activation. Utilizing a recently developed technique for detection of endogenous, GTP-bound Rap1, we have found that Rap1, but not Rap2, is transiently activated following T cell receptor stimulation of normal human T lymphocytes. Increases in intracellular calcium is both necessary and sufficient to induce Rap1 activation. Remarkably, costimulation of T cells with mitogenic anti-CD28 antibody completely abolished T cell receptor-dependent activation of Rap1. This report demonstrates a potential role for Rap1 in T cell receptor signaling and suggests inactivation of Rap1 as a candidate target of CD28-dependent costimulatory signals required for T cell antigen responsiveness.
Reedquist
K A
KA
Laboratory for Physiological Chemistry, Utrecht University, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands.
Bos
J L
JL
D018106:CD28 Antigens / Q000378:metabolism*; D017252:CD3 Complex / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism*; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism; D020668:rap GTP-Binding Proteins
D018106:CD28 Antigens; D017252:CD3 Complex; D011948:Receptors, Antigen, T-Cell; D019204:GTP-Binding Proteins; D020668:rap GTP-Binding Proteins; D002118:Calcium